Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease
Henne Holstege (Vrije Universiteit Amsterdam, Netherlands Institute for Neuroscience, TU Delft - Intelligent Systems)
M.J. Hulsman (Netherlands Institute for Neuroscience, TU Delft - Information management, Vrije Universiteit Amsterdam)
Camille Charbonnier (Université Rouen Normandie, Rouen)
Banjamin Grenier-Boley (Université de Lille)
Olivier Quenez (Université Rouen Normandie, Rouen)
Detelina Grozeva (Cardiff University)
Jeroen G.J. Van Rooij (Rotterdam Eye Hospital, Erasmus MC)
M.J.T. Reinders (TU Delft - Pattern Recognition and Bioinformatics)
S.J. Van der Lee (TU Delft - Pattern Recognition and Bioinformatics)
More Authors (External organisation)
More Info
expand_more
Other than for strictly personal use, it is not permitted to download, forward or distribute the text or part of it, without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license such as Creative Commons.
Abstract
Alzheimer’s disease (AD), the leading cause of dementia, has an estimated
heritability of approximately 70%1. The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants2. Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals—16,036 AD cases and 16,522 controls. Next to variants in TREM2, SORL1 and ABCA7, we observed a significant association of rare, predicted damaging variants in ATP8B4 and ABCA1 with AD risk, and a suggestive signal in ADAM10. Additionally, the rare-variant burden in RIN3, CLU, ZCWPW1 and ACE highlighted these genes as potential drivers of respective AD-genome-wide association study loci. Variants associated with the strongest effect on AD risk, in particular loss-of-function variants, are enriched in early-onset AD cases. Our results provide additional evidence for a major role for amyloid-β precursor protein processing, amyloid-β aggregation, lipid metabolism and microglial function in AD.
help_outline